Drug Delivery with Polymeric Nanocarriers—Cellular Uptake Mechanisms
Identifieur interne : 000E38 ( Ncbi/Merge ); précédent : 000E37; suivant : 000E39Drug Delivery with Polymeric Nanocarriers—Cellular Uptake Mechanisms
Auteurs : Levi Collin Nelemans ; Leonid GurevichSource :
- Materials [ 1996-1944 ] ; 2020.
Abstract
Nanocarrier-based systems hold a promise to become “Dr. Ehrlich’s Magic Bullet” capable of delivering drugs, proteins and genetic materials intact to a specific location in an organism down to subcellular level. The key question, however, how a nanocarrier is internalized by cells and how its intracellular trafficking and the fate in the cell can be controlled remains yet to be answered. In this review we survey drug delivery systems based on various polymeric nanocarriers, their uptake mechanisms, as well as the experimental techniques and common pathway inhibitors applied for internalization studies. While energy-dependent endocytosis is observed as the main uptake pathway, the integrity of a drug-loaded nanocarrier upon its internalization appears to be a seldomly addressed problem that can drastically affect the uptake kinetics and toxicity of the system in vitro and in vivo.
Url:
DOI: 10.3390/ma13020366
PubMed: 31941006
PubMed Central: 7013754
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Drug Delivery with Polymeric Nanocarriers—Cellular Uptake Mechanisms</title><author><name sortKey="Nelemans, Levi Collin" sort="Nelemans, Levi Collin" uniqKey="Nelemans L" first="Levi Collin" last="Nelemans">Levi Collin Nelemans</name></author><author><name sortKey="Gurevich, Leonid" sort="Gurevich, Leonid" uniqKey="Gurevich L" first="Leonid" last="Gurevich">Leonid Gurevich</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31941006</idno><idno type="pmc">7013754</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013754</idno><idno type="RBID">PMC:7013754</idno><idno type="doi">10.3390/ma13020366</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000A59</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A59</idno><idno type="wicri:Area/Pmc/Curation">000A59</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000A59</idno><idno type="wicri:Area/Pmc/Checkpoint">000160</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000160</idno><idno type="wicri:Area/Ncbi/Merge">000E38</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Drug Delivery with Polymeric Nanocarriers—Cellular Uptake Mechanisms</title><author><name sortKey="Nelemans, Levi Collin" sort="Nelemans, Levi Collin" uniqKey="Nelemans L" first="Levi Collin" last="Nelemans">Levi Collin Nelemans</name></author><author><name sortKey="Gurevich, Leonid" sort="Gurevich, Leonid" uniqKey="Gurevich L" first="Leonid" last="Gurevich">Leonid Gurevich</name></author></analytic><series><title level="j">Materials</title><idno type="eISSN">1996-1944</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Nanocarrier-based systems hold a promise to become “Dr. Ehrlich’s Magic Bullet” capable of delivering drugs, proteins and genetic materials intact to a specific location in an organism down to subcellular level. The key question, however, how a nanocarrier is internalized by cells and how its intracellular trafficking and the fate in the cell can be controlled remains yet to be answered. In this review we survey drug delivery systems based on various polymeric nanocarriers, their uptake mechanisms, as well as the experimental techniques and common pathway inhibitors applied for internalization studies. While energy-dependent endocytosis is observed as the main uptake pathway, the integrity of a drug-loaded nanocarrier upon its internalization appears to be a seldomly addressed problem that can drastically affect the uptake kinetics and toxicity of the system in vitro and in vivo.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ulbrich, K" uniqKey="Ulbrich K">K. Ulbrich</name></author><author><name sortKey="Hola, K" uniqKey="Hola K">K. Holá</name></author><author><name sortKey="Subr, V" uniqKey="Subr V">V. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Materials (Basel)</journal-id><journal-id journal-id-type="iso-abbrev">Materials (Basel)</journal-id><journal-id journal-id-type="publisher-id">materials</journal-id><journal-title-group><journal-title>Materials</journal-title></journal-title-group><issn pub-type="epub">1996-1944</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31941006</article-id><article-id pub-id-type="pmc">7013754</article-id><article-id pub-id-type="doi">10.3390/ma13020366</article-id><article-id pub-id-type="publisher-id">materials-13-00366</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Drug Delivery with Polymeric Nanocarriers—Cellular Uptake Mechanisms</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-8715-244X</contrib-id><name><surname>Nelemans</surname><given-names>Levi Collin</given-names></name></contrib><contrib contrib-type="author"><name><surname>Gurevich</surname><given-names>Leonid</given-names></name><xref rid="c1-materials-13-00366" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-materials-13-00366">Department of Materials and Production, Aalborg University, 9220 Aalborg, Denmark;<email>levinelemans@gmail.com</email></aff><author-notes><corresp id="c1-materials-13-00366"><label>*</label>Correspondence: <email>lg@mp.aau.dk</email></corresp></author-notes><pub-date pub-type="epub"><day>13</day><month>1</month><year>2020</year></pub-date><pub-date pub-type="collection"><month>1</month><year>2020</year></pub-date><volume>13</volume><issue>2</issue><elocation-id>366</elocation-id><history><date date-type="received"><day>20</day><month>12</month><year>2019</year></date><date date-type="accepted"><day>09</day><month>1</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 by the authors.</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Nanocarrier-based systems hold a promise to become “Dr. Ehrlich’s Magic Bullet” capable of delivering drugs, proteins and genetic materials intact to a specific location in an organism down to subcellular level. The key question, however, how a nanocarrier is internalized by cells and how its intracellular trafficking and the fate in the cell can be controlled remains yet to be answered. In this review we survey drug delivery systems based on various polymeric nanocarriers, their uptake mechanisms, as well as the experimental techniques and common pathway inhibitors applied for internalization studies. While energy-dependent endocytosis is observed as the main uptake pathway, the integrity of a drug-loaded nanocarrier upon its internalization appears to be a seldomly addressed problem that can drastically affect the uptake kinetics and toxicity of the system in vitro and in vivo.</p></abstract><kwd-group><kwd>drug delivery systems</kwd><kwd>endocytosis</kwd><kwd>polymeric micelles</kwd><kwd>amphiphilic block copolymers</kwd><kwd>nanoparticles</kwd><kwd>drug release</kwd></kwd-group></article-meta></front><floats-group><fig id="materials-13-00366-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Above the critical aggregation concentration, amphiphilic block copolymers self-assemble into a micellular structure (adapted from Reference [<xref rid="B8-materials-13-00366" ref-type="bibr">8</xref>] with permission from Elsevier).</p></caption><graphic xlink:href="materials-13-00366-g001"></graphic></fig><fig id="materials-13-00366-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Overview of uptake and internal trafficking via various endocytic pathways in a typical eukaryotic cell, with an estimated maximum uptake size for different pinocytosis mechanisms (reproduced from Reference [<xref rid="B24-materials-13-00366" ref-type="bibr">24</xref>] with permission from The Royal Society of Chemistry).</p></caption><graphic xlink:href="materials-13-00366-g002"></graphic></fig><fig id="materials-13-00366-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Uptake mechanisms of mammalian cells: (<bold>A</bold>) phagocytosis, <bold>(B</bold>) macropinocytosis, (<bold>C</bold>) clathrin-mediated endocytosis and (<bold>D</bold>) caveolae-mediated endocytosis. See text for more details. (Reproduced from Reference [<xref rid="B32-materials-13-00366" ref-type="bibr">32</xref>] with permission from The Royal Society of Chemistry).</p></caption><graphic xlink:href="materials-13-00366-g003"></graphic></fig><fig id="materials-13-00366-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Opsonization of nanoparticles in the bloodstream will lead to rapid clearing by the reticuloendothelial system via phagocytic uptake of the particles by macrophages (reproduced from Reference [<xref rid="B39-materials-13-00366" ref-type="bibr">39</xref>] with permission from Elsevier).</p></caption><graphic xlink:href="materials-13-00366-g004"></graphic></fig><fig id="materials-13-00366-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>(<bold>A</bold>) Uptake of Pheophorbide-a (Pheo) loaded, PEO-b-PCL micelles might follow the collisional or diffusional kinetic mechanism. Which describes the free aqueous concentration of nanoparticles (NP), Pheo (PF), vesicles (V); Pheo associated to nanoparticles (PNP), vesicles (PV) and the Pheo-Nanoparticle-Vesicle complex (NP-P-V). (<bold>B</bold>) Pheo shows a different emission spectrum when present in DOPC vesicles (solid), nanoparticles (dashed) or phosphate buffered salin (PBS) (dotted), which can be used to investigate the uptake mechanisms of PEO-b-PCL micelles (reprinted from Reference [<xref rid="B111-materials-13-00366" ref-type="bibr">111</xref>] with permission from Elsevier).</p></caption><graphic xlink:href="materials-13-00366-g005"></graphic></fig><fig id="materials-13-00366-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>(<bold>A</bold>) Confocal fluorescence image of KB cells incubated with DiO/DiI loaded micelles. The image shows the loss of Förster resonance energy transfer on the cell surface and intracellular space. (<bold>B</bold>) Normalized spectra of the measured fluorescent signal outside (red) and inside (green) the cells. (Scale bar: 10 µm.) (Adapted from Reference [<xref rid="B49-materials-13-00366" ref-type="bibr">49</xref>], Copyright 2008 National Academy of Sciences).</p></caption><graphic xlink:href="materials-13-00366-g006"></graphic></fig><fig id="materials-13-00366-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>Förster resonance energy transfer will only occur if the micelles release their core loaded drug (Nile red, acceptor) into the DAF (donor) labelled cell membrane (Adapted from Reference [<xref rid="B107-materials-13-00366" ref-type="bibr">107</xref>] with permission from Elsevier).</p></caption><graphic xlink:href="materials-13-00366-g007"></graphic></fig><table-wrap id="materials-13-00366-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">materials-13-00366-t001_Table 1</object-id><label>Table 1</label><caption><p>Overview of commonly used endocytic inhibitors, their effects and limitations [<xref rid="B40-materials-13-00366" ref-type="bibr">40</xref>,<xref rid="B44-materials-13-00366" ref-type="bibr">44</xref>,<xref rid="B45-materials-13-00366" ref-type="bibr">45</xref>,<xref rid="B46-materials-13-00366" ref-type="bibr">46</xref>].</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Agent</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mechanism Affected <sup>1</sup></th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Effect</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Limitation</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ref.</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Low temp (4 degrees)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">All energy dependent processes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Slows down/inhibits all energy dependent processes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Low temperature may influence fluidity of cell membrane</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B47-materials-13-00366" ref-type="bibr">47</xref>,<xref rid="B48-materials-13-00366" ref-type="bibr">48</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sodium azide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">All energy dependent processes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibits respiratory system of cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Toxic at higher concentrations</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B49-materials-13-00366" ref-type="bibr">49</xref>,<xref rid="B50-materials-13-00366" ref-type="bibr">50</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chlorpromazine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Translocates clathrin and AP2 from the cell surface to intracellular endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Not efficient in all cell lines, might interfere with the biogenesis of intracellular vesicles</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B51-materials-13-00366" ref-type="bibr">51</xref>,<xref rid="B52-materials-13-00366" ref-type="bibr">52</xref>,<xref rid="B53-materials-13-00366" ref-type="bibr">53</xref>] [<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (pp. 19–20)</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cytosol acidification</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibits the budding-off of clathrin- coated pits from the membrane</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Interferes with macropinocytosis and the actin cytoskeleton</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (p. 19)</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hypertonic sucrose</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Removes plasma membrane-associated clathrin lattices</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nonspecific, interferes with fluid phase macropinocytosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (pp. 17–18) [<xref rid="B55-materials-13-00366" ref-type="bibr">55</xref>,<xref rid="B56-materials-13-00366" ref-type="bibr">56</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Monodansylcadaverine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Stabilizes clathrin-coated pits</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Induces global changes in actin dynamics</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (p. 20)</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phenylarsine oxide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mechanisms unknown, possibly a tyrosine phosphate inhibitor</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Also inhibits micropinocytosis and is toxic at higher concentrations</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B57-materials-13-00366" ref-type="bibr">57</xref>,<xref rid="B58-materials-13-00366" ref-type="bibr">58</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Potassium depletion</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Removes plasma membrane-associated clathrin lattices</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nonspecific; affects actin cytoskeleton</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (p. 18) [<xref rid="B59-materials-13-00366" ref-type="bibr">59</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Dynasore</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CME, CvME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibitor of dynamin (small GTPase)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Has other off-target effects, including inhibition of membrane ruffling</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B60-materials-13-00366" ref-type="bibr">60</xref>,<xref rid="B61-materials-13-00366" ref-type="bibr">61</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Genistein</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CvME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibitor of several tyrosine kinases, causes disruption of the actin network</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Affects several uptake processes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B62-materials-13-00366" ref-type="bibr">62</xref>,<xref rid="B63-materials-13-00366" ref-type="bibr">63</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Okadaic acid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CvME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Phosphatase inhibitor, stimulates trafficking and internalization of caveolae</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nonspecific, off-target effects</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B64-materials-13-00366" ref-type="bibr">64</xref>]</td></tr><tr><td colspan="5" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Cholesterol inhibitors</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Filipin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CvME, Lipid raft</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Binds to cholesterol in the membrane</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Unstable and toxic, cholesterol influences other endocytic pathways besides CvME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (pp. 23–24) [<xref rid="B65-materials-13-00366" ref-type="bibr">65</xref>,<xref rid="B66-materials-13-00366" ref-type="bibr">66</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Statins</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CvME, Lipid raft</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lowering of cholesterol formation by inhibiting the enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nonspecific, many off-target effects</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (p. 22) [<xref rid="B67-materials-13-00366" ref-type="bibr">67</xref>,<xref rid="B68-materials-13-00366" ref-type="bibr">68</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Methyl-β-cyclodextrin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CvME, Lipid raft</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Removes cholesterol out of the plasma membrane by forming soluble inclusion complexes with cholesterol</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nonspecific, interferes with fluid phase endocytosis and CME, might induce membrane curvature</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (pp. 22–23) [<xref rid="B69-materials-13-00366" ref-type="bibr">69</xref>,<xref rid="B70-materials-13-00366" ref-type="bibr">70</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nystatin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CvME, Lipid raft</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Binds to cholesterol in the membrane</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Toxic</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (pp. 23–24)</td></tr><tr><td colspan="5" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>(Endosome) acidification inhibitors</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Monensin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prevents acidification of endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Acts as an ionophor, thereby inhibiting the acidification of endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B71-materials-13-00366" ref-type="bibr">71</xref>,<xref rid="B72-materials-13-00366" ref-type="bibr">72</xref>,<xref rid="B73-materials-13-00366" ref-type="bibr">73</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nigericin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prevents acidification of endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Acts as an ionophor, thereby inhibiting the acidification of endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B74-materials-13-00366" ref-type="bibr">74</xref>,<xref rid="B75-materials-13-00366" ref-type="bibr">75</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bafilomycin A1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prevents acidification of endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibits the vacuolar ATPase endosomal proton pump.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes. Potentially inhibits Ca<sup>2+</sup> pump SERCA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B76-materials-13-00366" ref-type="bibr">76</xref>,<xref rid="B77-materials-13-00366" ref-type="bibr">77</xref>,<xref rid="B78-materials-13-00366" ref-type="bibr">78</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Prevents acidification of endosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Increases pH of acidic vesicles (e.g., lysosomes), possibly inhibits some lysosomal hydrolases</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Affects many other cellular processes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B79-materials-13-00366" ref-type="bibr">79</xref>,<xref rid="B80-materials-13-00366" ref-type="bibr">80</xref>] (pp. 49–54)</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Amiloride</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Macropinocytosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibits macropinocytosis by lowering submembranous pH (cytosolic pH close to the membrane) and prevents Rac1 and Cdc42 signaling.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B81-materials-13-00366" ref-type="bibr">81</xref>,<xref rid="B82-materials-13-00366" ref-type="bibr">82</xref>,<xref rid="B83-materials-13-00366" ref-type="bibr">83</xref>]</td></tr><tr><td colspan="5" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>F-actin inhibitors</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cytochalasin D</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Macropinocytosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibits actin polymerization and may thus lead to actin filament disassembly</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nonspecific, may affect other endocytic processes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (p. 26) [<xref rid="B84-materials-13-00366" ref-type="bibr">84</xref>,<xref rid="B85-materials-13-00366" ref-type="bibr">85</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Jasplakinolide</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Macropinocytosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Stabilizes actin and promotes actin assembly</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Various effects depending on cell line and assay conditions</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B84-materials-13-00366" ref-type="bibr">84</xref>,<xref rid="B86-materials-13-00366" ref-type="bibr">86</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Latrunculin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Macropinocytosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sequesters actin monomers, blocks actin polymerization and may thus lead to actin filament disassembly</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Not necessarily efficient in adherent cells</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (p. 26) [<xref rid="B87-materials-13-00366" ref-type="bibr">87</xref>,<xref rid="B88-materials-13-00366" ref-type="bibr">88</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Swinholide A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Macropinocytosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Has F-actin severing activity</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nonspecific, may affect other endocytic processes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B86-materials-13-00366" ref-type="bibr">86</xref>,<xref rid="B89-materials-13-00366" ref-type="bibr">89</xref>]</td></tr><tr><td colspan="5" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Phosphoinositide 3-kinase inhibitors</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LY294002</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Macropinocytosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibits phosphatidylinositol 3-kinase class I and III</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nonspecific, also affects CME and CvME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (pp. 26–27) [<xref rid="B90-materials-13-00366" ref-type="bibr">90</xref>,<xref rid="B91-materials-13-00366" ref-type="bibr">91</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Wortmannin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Macropinocytosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibits phosphatidylinositol 3-kinase class I and III</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nonspecific, also affects CME and CvME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (pp. 26–27) [<xref rid="B90-materials-13-00366" ref-type="bibr">90</xref>,<xref rid="B91-materials-13-00366" ref-type="bibr">91</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3-methyladenine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Macropinocytosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibits phosphatidylinositol 3-kinase class III</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nonspecific, also affects CME and CvME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-materials-13-00366" ref-type="bibr">54</xref>] (pp. 26–27) [<xref rid="B92-materials-13-00366" ref-type="bibr">92</xref>]</td></tr></tbody></table><table-wrap-foot><fn><p><sup>1</sup> Abbreviations: Clathrin-mediated endocytosis (CME), Caveolae-mediated endocytosis (CvME).</p></fn></table-wrap-foot></table-wrap><table-wrap id="materials-13-00366-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">materials-13-00366-t002_Table 2</object-id><label>Table 2</label><caption><p>Overview of the proposed uptake mechanisms of different polymeric micelles.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Material <sup>1,2</sup></th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Uptake Mechanism(s) <sup>1</sup></th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Cell type <sup>3</sup></th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Drug <sup>1</sup></th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Comments</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ref.</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mixed micelles:<break></break>TPGS2K, HS15, F127</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Energy dependent<break></break>CME<break></break>CvME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Caco-2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Curcumin<break></break>DOX</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Only analyzed uptake of drug</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B93-materials-13-00366" ref-type="bibr">93</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">OCC</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CME<break></break>CvME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Caco-2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Silybin<break></break>Rhodamine-123</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Only analyzed uptake of drug</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B94-materials-13-00366" ref-type="bibr">94</xref>,<xref rid="B95-materials-13-00366" ref-type="bibr">95</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">OGC<break></break>SH-OGC</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CME<break></break>CvME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Caco-2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Paclitaxel<break></break>Rhodamine-123</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Only analyzed uptake of drug</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B96-materials-13-00366" ref-type="bibr">96</xref>,<xref rid="B97-materials-13-00366" ref-type="bibr">97</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">P(PEGMEMA)<sub>75u</sub>-b-PMMA<sub>80u</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Clathrin and caveolae independent<break></break>CME<break></break>CvME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">WiDr</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOX<break></break>NileRed</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">80% of the uptake was via a different, undefined uptake mechanism</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B106-materials-13-00366" ref-type="bibr">106</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEG<sub>2000</sub>-b-PLGA<sub>5000</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Energy dependent<break></break>CME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Calu-3<break></break>NCI-H441</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NileRed<break></break>Curcumin acetate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Only analyzed uptake of drug</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B98-materials-13-00366" ref-type="bibr">98</xref>,<xref rid="B99-materials-13-00366" ref-type="bibr">99</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEG<sub>3000/2000/5000</sub>-PLA<sub>40000</sub><break></break>PEG<sub>2000/5000</sub>-PLGA<sub>40000</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Energy dependent<break></break>Lipid raft mediated</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Caco-2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Curcumin<break></break>Coumarin 6</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Only analyzed uptake of drug</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B100-materials-13-00366" ref-type="bibr">100</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEG<sub>5000</sub>-b-PLA<sub>5000</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Direct drug transfer to cell membrane<break></break>Energy dependent<break></break>Caveolae/lipid raft-mediated endocytosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A2780</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Paclitaxel<break></break>NileRed<break></break>FRET, DAF/NileRed</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B5-materials-13-00366" ref-type="bibr">5</xref>,<xref rid="B107-materials-13-00366" ref-type="bibr">107</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEG-b-PLGA</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CvME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MCF-7</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DTX, 3-MA, CQ<break></break>Coumarin 6</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Only analyzed uptake of drug</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B6-materials-13-00366" ref-type="bibr">6</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEO<sub>2000/5000/13000</sub>-b-PCL<sub>5000</sub><break></break>PEO<sub>5000</sub>-b-PCL<sub>13000/24000</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MCF-7</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DiIC</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEO5000-b-PCL13000 showed fastest uptake, only analyzed drug uptake</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B101-materials-13-00366" ref-type="bibr">101</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEO<sub>2000</sub>-b-PCL<sub>2600/2800</sub><break></break>PEO<sub>5000</sub>-b-PCL<sub>4000</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Direct drug transfer to cell membrane</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HCT-116</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pheo<break></break>Conjugated Fluorescein</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B108-materials-13-00366" ref-type="bibr">108</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEO<sub>45u</sub>-b-PCL<sub>23u</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Energy dependent<break></break>CME</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">P19</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Conjugated Rhodamine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B3-materials-13-00366" ref-type="bibr">3</xref>,<xref rid="B109-materials-13-00366" ref-type="bibr">109</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEO<sub>44u</sub>-b-PCL<sub>20u</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Temperature, pH and energy dependent</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PC12</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DiIC</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Only analyzed uptake of drug</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B110-materials-13-00366" ref-type="bibr">110</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEO<sub>5000</sub>-b-PCL<sub>2000</sub><break></break>PEO<sub>5000</sub>-b-PDLLA<sub>5000</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Direct drug transfer to cell membrane</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">KB</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DiIC/DiOC<break></break>Conjugated Fluorescein</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B49-materials-13-00366" ref-type="bibr">49</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEO<sub>5000</sub>-b-PCL<sub>4000</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Direct drug transfer to cell membrane</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MCF-7</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pheo<break></break>DiIC/DiOC</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Micelle uptake is slow (>4 hr), while release of drug is fast</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B111-materials-13-00366" ref-type="bibr">111</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEOz<sub>6000</sub>-b-PLA<sub>1100/2200/3900/8500/10000/13700</sub> PEOz<sub>2600/3300/4500/5600/6700/8900</sub>-b-PLA<sub>4000</sub></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Energy dependent<break></break>Cholesterol dependent<break></break>Caveolae/lipid raft-mediated endocytosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MCF-7</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Paclitaxel<break></break>Conjugated DEC</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEOz/PLA ratio of 1.7-2.0 for optimal uptake</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B17-materials-13-00366" ref-type="bibr">17</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Val-TPGS<break></break>Phe-TPGS</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Energy dependent<break></break>CvME<break></break>CME<break></break>Macropinocytosis</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Caco-2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Curcumin<break></break>Coumarin 6</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Enhanced transport across intestinal epithelial barrier, Only analyzed uptake of drug</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B47-materials-13-00366" ref-type="bibr">47</xref>]</td></tr></tbody></table><table-wrap-foot><fn><p><sup>1</sup> Abbreviations: N-octyl-O, N-carboxymethyl chitosan (OCC), N-mercapto acetyl-N′-octyl-O, N″-glycol chitosan (OGC), poly(poly(ethylene glycol) methyl ether methacrylate)(P(PEGMEMA)), poly(methyl methacrylate) (PMMA), Poly(ethylene glycol)/poly(ethylene oxide) (PEG/PEO), poly(lactide-co-glycolide) (PLGA), poly(lactide) (PLA), poly(ε-caprolactone) (PCL), poly((D,L-lactide) (PDLLA), poly(2-ethyl-2-oxazoline) (PEOz), D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), Clathrin-mediated endocytosis (CME), Caveolae-mediated endocytosis (CvME), Doxorubicin (DOX), 5-dodecanoylaminofluorescein (DAF), Docetaxel (DTX), 3-methyladenine (3-MA), Chloroquine (CQ), 1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindocarbocyanine Perchlorate (DiIC), Pheophorbide-a (Pheo), 3,3′-Dihexyloxacarbocyanine Iodide (DiOC), 7-N,N-diethylamino-coumarin-3 (DEC). <sup>2</sup> When available, the average molecular weight of the polymer block is listed (Dalton). If the number of monomeric units was provided, it is denoted by a number followed by ‘u.’ If different sizes of the same polymer were used, they are listed separated by ‘/.’ <sup>3</sup> Information on the various cell lines: human colon cancer cell lines (Caco-2 and WiDr, HCT-116), human lung cancer cell lines (Calu-3 and NCI-H441), human ovarian cancer cell line (A2780), human breast cancer cell line (MCF-7), mouse pluripotent embryonic carcinoma cell line (P19), pheochromocytoma rat cell line (PC12), HeLa contaminant human tumor cell line (KB).</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list></list><tree><noCountry><name sortKey="Gurevich, Leonid" sort="Gurevich, Leonid" uniqKey="Gurevich L" first="Leonid" last="Gurevich">Leonid Gurevich</name><name sortKey="Nelemans, Levi Collin" sort="Nelemans, Levi Collin" uniqKey="Nelemans L" first="Levi Collin" last="Nelemans">Levi Collin Nelemans</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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